Involvement of Reelin and Cajal-Retzius Cells in the Developmental Formation of Vertical Columnar Structures in the Cerebral Cortex: Evidence from the Study of Mouse Presubicular Cortex

Abstract

The mammalian cerebral cortex is organized into horizontal and vertical arrays of neurons and their fiber connections that form anatomically and physiologically distinct laminar and columnar compartments. However, the developmental mechanism(s) underlying this dichotomous pattern remains a mystery. We provide anatomical evidence suggesting that reelin, a diffusible protein produced and secreted by Cajal-Retzius cells, is involved in the developmental formation of the vertical cell structures in the mouse presubicular cortex, the unique site where the vertical columnar arrays of cortical plate neurons and their dendritic branches are clearly identified during the early postnatal period. Our results also suggest that reelin plays a role in the formation of these vertical structures by acting as an inhibitory or stop signal for cortical plate neurons and their dendritic extensions. In addition to having perturbed horizontal laminae, reeler mutant mice, lacking reelin, display disruption of these vertical structures. Based on the present findings, we hypothesize that reelin and Cajal-Retzius cells regulate the developmental formation of not only horizontal laminations, but also vertical columnar structures in the cerebral cortex.

Early Serotonergic Projections to Cajal-Retzius Cells: Relevance for Cortical Development

“…Because the manipulation of the serotonergic system altered brain reelin levels, it also could have an effect on the late embryonic stages of cortical laminar and columnar development, which depend on Cajal-Retzius cells and their transient networks (Marín-Padilla, 1998;Nishikawa et al, 2002;Luhmann et al, 2003). To see if supragranular cortical layers were affected in young pups (postnatal day 7) exposed to 5-MT before birth, we analyzed their presubicular cortex, which has visible supragranular columns in early postnatal life (Van Groen and Wyss, 1990;Nishikawa et al, 2002).…”

“…Specifically, it has been proposed that they may form contacts with Cajal-Retzius (CR) cells (Radnikow et al, 2002), but no actual synaptic contacts have so far been demonstrated. CR cells are located in the MZ and are considered to be necessary for the correct positioning of neurons in cortical layers (Ogawa et al, 1995;Marín-Padilla, 1998;Dulabon et al, 2000;Hack et al, 2002;Ang et al, 2003;Rakic and Zecevic, 2003), as well as in radial columns (Nishikawa et al, 2002;Luhmann et al, 2003). Because microcolumns are basic anatomical and functional units of the cerebral cortex (Jones, 2000;Buxhoeveden and Casanova, 2002), their abnormalities underlie several neurological disorders in humans.…”

The N-terminal region of reelin regulates postnatal dendritic maturation of cortical pyramidal neurons

“…Both serotonin and Cajal-Retzius cells have been implicated in the formation of cortical columns (16,17). Nishikawa et al (16) postulated that reelin regulation of early postnatal maturation of dendritic arborization is involved in the development of vertical columnar structures in the mouse presubicular cortex. They hypothesized that reelin may act as a stop signal for growth and branching of apical dendrites.…”

“…It has been suggested that, in addition to their role in migration and positioning of postmitotic neurons, reelin-secreting neurons are also involved in the formation of vertical cortical columns. For example, the reeler mouse, an autosomal recessive mutant in which reelin is defective, displays abnormalities in presubicular columns, which led Nishikawa et al (16) to postulate that reelin may act as a stop signal for dendritic extensions of cortical neurons. In addition, Janusonis et al (17) showed that serotonergic input on Cajal-Retzius cells is important for proper corticogenesis, as disruption of the serotonergic system during embryonic development results in lower levels of whole-brain reelin and a disturbed formation of cortical columns in the presubicular cortex.…”

Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: towards an integration of molecular and morphologic aspects of the neurodevelopmental hypothesis

“…32 Reelin is a key molecule during corticogenesis, guiding the migration and positioning of proliferating neurons, and influencing cortical lamination, columnarity, and synaptic connectivity. [33][34][35][36] During development, reelin is secreted by Cajal-Retzius cells in the marginal zone. [37][38][39] It is a serine protease, 40 and acts upon neurons, and maybe glia, 41 via several receptor-mediated mechanisms.…”